ESTROGEN AND PROGESTERONE 



561 



four experimental animals the only well de- 

 veloped fundus was found in the animal on 

 the shortest treatment, i.e., 60 days. 



The mitotic activity in the epithelium of 

 the glands and surface mucosa also indicates 

 a limited effect of estrogen. This can be 

 demonstrated to best advantage in the endo- 

 metria of castrated monkeys that have been 

 on estrogen for different lengths of time and 

 have received an injection of colchicine 8 

 hours before their uteri were removed. A 

 comparison of the number of cells in mitosis 

 per square centimeter of surface mucosa at 

 10, 30, 45, and 60 days is shown in Figure 

 9.3. From this it can be seen that mitotic 

 activity approaches that in a castrated ani- 

 mal. Although the five points used in draw- 

 ing the curve are quite inadequate for an 

 accurate analysis of the mitotic response in 

 the epithelial components of the endome- 

 trium, they do show that cell division is 

 most rapid soon after the beginning of an 

 estrogen treatment and subseciuently de- 

 clines. 



The loss of responsiveness of the endome- 

 trium to estrogen seems related more to the 

 length of treatment than to dosage of hor- 

 mone. An endometrium of normal thickness 

 can be produced in 2 or 3 weeks at a dosage 

 level of estrogen that will not maintain the 

 growth induced for longer than about 40 

 days without bleeding (Hisaw, 1935; Engle 

 and Smith, 1935; Zuckerman, 1937b). The 

 response to a low dosage of estrogen that 

 will prevent bleeding during the course of 

 treatment (about 10 /xg. estradiol-17/8 daily) 

 is one of rapid endometrial growth at first, 

 as has been described, followed by a thin- 

 ning of the endometrium. The refractoriness 

 of the endometrium to estrogen becomes so 

 pronounced after about 100 days of treat- 

 ment that very few cell divisions are seen in 

 the epithelium of the glands and surface 

 mucosa. The general morphology of the en- 

 dometrium retains the characteristic ap- 

 pearance of the follicular phase of the men- 

 strual cycle except that the stroma is 

 usually more dense and the cells of the 

 glandular epithelium have large deposits of 

 glycogen between the nucleus and the base- 

 ment membrane. However, metabolically 

 such endometria are surprisingly inactive. 

 Although they are dependent on the pres- 

 ence of estrogen and may bleed within about 



Mitotic Response of 

 Uterine Lpithelium 

 TO looo I. u. Estrogen 

 PER D«y. 



Fig. 9.3. The number of mitoses per square centi- 

 meter of surface epithelium of the endometrium in 

 a castrated monkey and in four castrated animals 

 given 10 /xg. estradiol daily for 10, 30, 45, and 60 

 days, respectively. One-tenth of actual number of 

 mitoses is shown on the ordinate. (From F. L. 

 Hisaw, in A Symposium on Steroid Hormones, Uni- 

 versity of Wisconsin Press, 1950.) 



48 hours if the treatment is stopped, the 

 activity of their oxidative enzymes and the 

 ratio of nucleoproteins (RNA:DNA) are 

 about the same as in the involuted endome- 

 tria of castrated animals. 



The effects that accompany moderate es- 

 trogenic stimulation become exaggerated in 

 several respects when large doses of estrogen 

 are given for an extended period. The dis- 

 parity between the area of myometrium and 

 endometrium becomes greater as the treat- 

 ment progresses (Fig. 9.4). Kaiser (1947) 

 described the destruction of the spiraled 

 arterioles of the endometrium in monkeys 

 given large doses of estrogen and Hartman, 

 Geschickter and Speert (1941) reported the 

 reduction of the reproductive tract to the 

 size of that of a juvenile animal by the end 

 of 18 months during which injections of 

 large doses of estrogen were supplemented 

 by subcutaneous implantation of estrogen 

 pellets. These observations not only show 

 that the endometrium becomes unresponsive 

 to estrogen when the treatment is prolonged 

 but that large doses produce injurious ef- 

 fects. 



